Rajasekar Reddy Annapureddy

A ligand accelerated highly efficient palladium-catalyzed C–H arylation of electron-deficient polyfluoroarenes with aryl and heteroaryl bromides has been developed. The reaction proceeds efficiently under mild conditions with low catalyst loading (0.25 mol % Pd) and ligand loading (0.275 mol %), affording a broad range of fluorinated biaryl products in good to excellent yields. The methodology exhibits a wide substrate scope and good functional group tolerance. Its synthetic utility is demonstrated through the concise synthesis of several industrially relevant molecules, highlighting the practicality, efficiency, and scalability of the catalytic system.

A telescoped two-step fully continuous-flow process for the synthesis of nevirapine (trade name: Viramune), a key therapeutic agent for the prevention and treatment of HIV-1 infection, has been developed. The process employs, for the first time, sodium bis(trimethylsilyl)amide (NaHMDS) as a homogeneous, process-friendly base for both reaction stages and enables direct conversion of methyl 2-(cyclopropylamino)nicotinate and 2-chloro-3-amino-4-picoline to nevirapine without isolation of the cyclization intermediate. The optimized process operates with a total residence time of 10 min and delivers crude nevirapine in 91.9% overall isolated yield across two reaction steps, with a space-time yield of ∼365 g/h/L and 99.6 A% HPLC purity. Furthermore, we developed an on-demand continuous generation of NaHMDS in diglyme (up to ∼2.0 M) using a sodium packed-bed column reactor. Using on-demand generated NaHMDS, the telescoped synthesis yielded crude nevirapine in 90.7% isolated yield (∼340 g/h/L space-time yield and 99.5 A% purity), providing a scalable and cost-effective alternative to NaH applied in the current commercial synthesis.

We report a mild lithium methoxide (LiOMe)-catalyzed protocol for the trifluoromethylation of aldehydes, acyclic and cyclic ketones, and α,β-unsaturated carbonyl compounds. This method avoids the use of fluorinated or strong bases that promote enolization, offering broad functional group tolerance, including silyl, Boc, Cbz, nitrile, and benzyl groups, enabling its application to diverse complex substrates. Additionally, LiOMe catalyzes the diastereoselective addition of CF₃ to chiral keto esters derived from (1R,2S)-1-(methylamino)-2,3-dihydro-1H-inden-2-ol, affording products with diastereomeric ratios up to 84:16.

We report pentafluorohalobenzene (C₆F₅I and C₆F₅Br) as an iodine or bromine transfer reagent for the generation of both electron-rich and electron-poor (hetero)aryl iodides and bromides with excellent chemo/regio selectivity in up to 95% yields. Continuous flow synthesis proved to be advantageous for this transformation. The iodine or bromine transfer occurs through treatment with in situ-generated (hetero)aryl Grignard reagents derived from aryl halides with C₆F₅I or C₆F₅Br. The resulting iodo- and chloro/bromo-pyridines were further transformed into bis-substituted pyridines through subsequent chemoselective coupling reactions.

We report a lateral sodiation of alkyl(hetero)arenes using on‐demand generated hexane‐soluble (2‐ethylhexyl)sodium (1) in the presence of TMEDA. (2‐Ethylhexyl)sodium (1) is prepared via a sodium packed‐bed reactor and used for metalations at ambient temperature in batch as well as in continuous flow. The resulting benzylic sodium species are subsequently trapped with various electrophiles including carbonyl compounds, epoxides, oxetane, allyl/benzyl chlorides, alkyl halides and alkyl tosylates. Wurtz‐type couplings with secondary alkyl halides and tosylates proceed under complete inversion of stereochemistry. Furthermore, the utility of this lateral sodiation is demonstrated in the synthesis of pharmaceutical relevant compounds. Thus, fingolimod is prepared from p‐xylene applying the lateral sodiation twice. In addition, 7‐fold isotopically labeled salmeterol‐d₇ and fenpiprane as well as precursors to super linear alkylbenzene (SLAB) surfactants are prepared.

Wir beschreiben eine laterale Natriierung von Alkali(hetero)arenen mittels bedarfsgerecht generiertem, in Hexan löslichem (2‐Ethylhexyl)natrium (1) in Gegenwart von TMEDA. (2‐Ethylhexyl)natrium (1) wird mittels eines Natrium‐Festbettreaktors hergestellt und für Metallierungen bei Umgebungstemperatur sowohl im Kolben als auch im kontinuierlichem Durchfluss genutzt. Die entstehenden benzylischen Natriumspezies werden nachfolgend mit verschiedenen Elektrophilen, unter anderem Carbonylverbindungen, Epoxiden, Oxetan, Allyl/Benzylchloriden, Alkylhalogenen und ‐tosylaten abgefangen. Wurtz‐Typ‐Kopplungen mit sekundären Alkylhalogenen und Tosylaten laufen unter kompletter Inversion der Stereochemie ab. Des Weiteren wird die Nützlichkeit dieser lateralen Natriierung durch die Synthese pharmazeutisch relevanter Verbindungen demonstriert. So wird Fingolimod durch die zweifache Anwendung der lateralen Natriierung ausgehend von p‐Xylol hergestellt. Zusätzlich ist 7‐fach Isotopen angereichertes Salmeterol‐d₇ und Fenpiprane, sowie Ausgangsmaterialien zu super linearen Alkylbenzyl (SLAB) Tensiden hergestellt worden.

We report the on‐demand generation of hexane‐soluble (2‐ethylhexyl)sodium (1) from 3‐(chloromethyl)heptane (2) using a sodium‐packed‐bed reactor under continuous flow conditions. Thus, the resulting solution of 1 is free of elemental sodium and therefore suited for a range of synthetic applications. This new procedure avoids the storage of an alkylsodium and limits the handling of metallic sodium to a minimum. (2‐Ethylhexyl)sodium (1) proved to be a very useful reagent and undergoes in‐line Br/Na‐exchanges as well as directed sodiations. The resulting arylsodium intermediates are subsequently trapped in batch with various electrophiles such as ketones, aldehydes, Weinreb‐amides, imines, allyl bromides, disulfides and alkyl iodides. A reaction scale‐up of the Br/Na‐exchange using an in‐line electrophile quench was also reported.